Johannes D. Veldhuis, MD


March 15, 2000

In This Article

Aging Cells

At the cellular level, several processes are involved in the physiology of aging and the development of some aging-related diseases. Apoptosis, a word coined in 1972, signifies the process of nontraumatic and noninflammatory cell death -- and the opposite of cell mitosis -- that balances cell proliferation and thus maintains homeostasis. This theme was adumbrated as early as the late 1800s in studies of ovarian follicular atresia. Specific gene products either promote (Bax) or oppose (Bcl-2) regulated cell death via mitochondrial effects.[2] Dysregulation of apoptosis has been implicated in the development of diseases that are more prevalent in older individuals, such as cancer and the neurodegenerative disorders (Alzheimer's and Parkinson's disease).

Telomeres have also been implicated in the regulation of cellular senescence. Telomeres consist of tandem repeats of a short nucleotide sequence and are located on the ends of chromosomes. Their length limits the total number of attainable cell generations in a tissue or organ (the so-called "end-replication" problem -- the inability of DNA polymerase to completely replicate the 3_ end of linear DNA). It has been speculated that the limited proliferative potential of human cells is a result of the telomere shortening that occurs during DNA synthesis at each cell division. The extension of telomeres by the enzyme telomerase compensates for the loss of a few nucleotides of telomeric DNA during each cell cycle, essentially protecting and ensuring that the entire linear chromosome is completely replicated. As a result, telomere length is directly related to the number of cell generations. Transfection of human cells with the gene for telomerase has resulted in more than 400 population doublings. Thus, telomere renewal may be relevant in both cancer pathogenesis and the research of aging.[3]

Biochemical insults also arise within aging cells, in part from the action of reactive oxygen species generated and scavenged incompletely throughout the cell cycle. Aging-associated changes also occur between and among cells via alterations in the intercellular matrix, the intercellular exchange of trophic factors, the release of inflammatory cytokine mediators, and the degree of infiltration by other associated cell types (eg, glial interactions with neurons). However, it is not known why free-radical damage does not adversely affect certain cells (eg, gonadal germ cells).[4]